Depression is one of the most common neurological disorders in the United States, affecting approximately 17% of the population with a clear sex difference. According to a current hypothesis, efficacy of antidepressant drugs depends on increased hippocampal neurogenesis, elicited after prolonged antidepressant medication. Since rapid changes in mood state that occur, e.g., at the onset of individual depressive episodes cannot be reconciled with slowly evolving neurogenetic alterations, an argument has been raised recently that antidepressant treatment might also involve a more rapid cellular plasticity mechanism that affects the integrity of the hippocampal neuronal circuitry. We have discovered that treatment of ovariectomized female rats with fluoxetine for 5 days elicits a robust increase in the density of dendritic spine synapses in the CA 1 hippocampal area and dentate gyrus, while spine synapse density increases of similar magnitude in the CAS area can be observed only after 14-day treatment. These spine synapse changes in CA 1 and dentate gyrus occur long before the first indications of increased dentate gyrus neurogenesis. Based on these data, we hypothesize that the mechanism of antidepressant action involves the induction of spine synapse formation in the hippocampus, leading to the restoration of the hippocampal neuronal circuitry and behavioral improvement. Since this same neuronal circuit is also a major target of gonadal steroid action, this mechanism may not only be associated with rapid changes in mood state, but also may provide an explanation for the sex and age differences in rates of depression and responses to antidepressant treatment. To test this hypothesis, we propose a combination of morphological and behavioral experiments in the rat that will investigate (a) the sequence and behavioral correlates of fluoxetine-induced hippocampal spine synapse changes; (b) the hippocampal synaptogenetic potential of several classes of antidepressants; (c) the neuronal substrates of the hippocampal synaptogenetic effect of several antidepressants; and (d) the possible sex and age differences in fluoxetine-induced hippocampal spine synapse changes. The experiments proposed in this application represent the first step in our effort to understand the role and significance of hippocampal synaptic remodeling in the neurobiology of depression and antidepressant therapy. [unreadable] [unreadable] [unreadable]